Project description:Specific gut microbiota is critically involved in metabolic diseases, including obesity. Through analysis of gut microbiota in diabetic patients and animal models, it was found that Romboutsia ilealis is closely associated with obesity. Here, our findings show that oral administration of Romboutsia ilealis significantly alleviates diet-induced obesity and metabolic dysfunction. Interestingly, this effect occurs not through modulation of food intake or energy expenditure, but by regulating lipid absorption and metabolism in the gut. Additionally, metabolomics analysis identified 2-oxindole-3-acetic acid (OAA) as the key metabolite involved in the regulation of obesity by Romboutsia ilealis. Its regulatory effect on intestinal lipid absorption was further validated both in vitro and in vivo. Mechanistically, using biotin-labeled OAA combined with proteomic analysis, we found that OAA directly interacts with the deubiquitin enzyme PSMD3, increasing the ubiquitination level of m6A binding protein YTHDF2 and reducing its protein stability, thereby enhancing intestinal lipid absorption. Furtherly, through m6A-seq, we discovered that YTHDF2 negatively regulates the expression of RXRB by recognizing the m6A sites on its mRNA, which in turn downregulates the expression of lipid absorption and transport proteins CD36 and FABP2, ultimately inhibiting intestinal lipid absorption. In summary, our findings reveal that Romboutsia ilealis and OAA regulate obesity-associated lipid accumulation through PSMD3-mediated deubiquitination of YTHDF2, suggesting that they represent novel prebiotics and probiotics with potential as therapeutic agents against obesity.
